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IFNγ Signaling is a Driver of Dnmt3a-Mutant Clonal Hematopoiesis

51 Pages Posted: 8 Apr 2020 Publication Status: Published

See all articles by Daniel Hormaechea Agulla

Daniel Hormaechea Agulla

Baylor College of Medicine - Section of Infectious Diseases

Katie A. Matatall

Baylor College of Medicine - Section of Infectious Diseases

Duy T. Le

Baylor College of Medicine

Bailee Kain

Baylor College of Medicine - Graduate Program in Translational Biology and Molecular Medicine

Xiaochen Long

Rice University

Pawel Kus

Silesian University of Technology

Roman Jaksik

Silesian University of Technology

Grant A. Challen

Washington University in St. Louis - Department of Medicine

Marek Kimmel

Rice University

Katherine Y. King

Baylor College of Medicine - Section of Infectious Diseases

More...

Abstract

Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We used a murine model to investigate the prediction that infection provides selective pressure favoring expansion of Dnmt3a-mutant hematopoietic stem cells (HSCs). We created Dnmt3a mosaic mice by transplanting a mixed population of Dnmt3a-mutant and WT HSCs into WT mice and observed substantial expansion of Dnmt3a-mutant HSCs during chronic mycobacterial infection. Transcriptional profiling and functional studies indicate reduced differentiation and reduced secondary stress-induced apoptosis account for Dnmt3a-mutant clonal expansion during infection. Both injection of recombinant IFNγ alone and infecting mice transplanted with HSCs lacking the differentiation factor Batf2 partially phenocopied CH by Dnmt3a-mutant HSCs upon infection. This is the first study demonstrating that IFNγ signaling induced during chronic infection can drive DNMT3A-mutant CH.

Keywords: clonal hematopoiesis, infection, interferon gamma, Dnmt3a, clonal competition

Suggested Citation

Hormaechea Agulla, Daniel and Matatall, Katie A. and Le, Duy T. and Kain, Bailee and Long, Xiaochen and Kus, Pawel and Jaksik, Roman and Challen, Grant A. and Kimmel, Marek and King, Katherine Y., IFNγ Signaling is a Driver of Dnmt3a-Mutant Clonal Hematopoiesis. Available at SSRN: https://ssrn.com/abstract=3564993 or http://dx.doi.org/10.2139/ssrn.3564993
This version of the paper has not been formally peer reviewed.

Daniel Hormaechea Agulla

Baylor College of Medicine - Section of Infectious Diseases ( email )

United States

Katie A. Matatall

Baylor College of Medicine - Section of Infectious Diseases ( email )

United States

Duy T. Le

Baylor College of Medicine

One Baylor Plaza
Apt 510
Houston, TX TX - Texas 77030
United States

Bailee Kain

Baylor College of Medicine - Graduate Program in Translational Biology and Molecular Medicine ( email )

Houston, TX 77030
United States

Xiaochen Long

Rice University

6100 South Main Street
Houston, TX 77005-1892
United States

Pawel Kus

Silesian University of Technology ( email )

Roosevelta str. 26
Zabrze, 41-800
Poland

Roman Jaksik

Silesian University of Technology ( email )

Roosevelta str. 26
Zabrze, 41-800
Poland

Grant A. Challen

Washington University in St. Louis - Department of Medicine

St. Louis, MO 63110
United States

Marek Kimmel

Rice University

6100 South Main Street
Houston, TX 77005-1892
United States

Katherine Y. King (Contact Author)

Baylor College of Medicine - Section of Infectious Diseases ( email )

United States

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